ON HEART TISSUE REENGINEERING ?
JC Chachques, MD PhDGeorges Pompidou European Hospital
Paris, France
Stem cell therapy and CV innovations
What’s new ?
Cardiac Bioassist - Cooperative Work
Teams :
• Olivier Schussler. Ottawa Heart Institut, Canada
• Carlos Semino. MIT + Barcelona Bioengineering Center
• Jorge Genovese. Pittsburgh University, USA
• Jorge Trainini. Avellaneda Hospital, Argentina
HEART FAILURE IN EUROPE
• Heart failure is the single biggest reason for acute hospital admission.
• Around 30 million people in Europe have heart failure and its incidence is increasing.
• More people are living to an old age, and more are surviving a heart attack but with damage to the heart.
PREVALENCE of HEART FAILURE in USA (total population: 305 millions)
Evidence for cardiomyocyte renewal in humans Science 2009; 324: 98-102
Frisen J. et al, Karolinska Institut, Stockholm, Sweden
• Cardiomyocytes are generated also later in life ? • Carbon-14, generated by nuclear bomb tests during the Cold
War, integrated into DNA allows to establish the age of cardiomyocytes in humans
• Results: cardiomyocytes renew, with a gradual decrease from 1% turning over annually at age of 25, to 0.45% at age of 75
• Fewer than 50% of cardiomyocytes are exchanged during a normal life span
• Perspectives: development of therapeutic strategies aimed at stimulating this process in cardiac pathologies
STEM CELL THERAPY and
BIOARTIFICIAL MYOCARDIUM
CARDIAC BIO-ASSIST
CELLS FOR MYOCARDIAL REGENERATION
• Skeletal myoblasts • Bone marrow mononuclear cells • Bone marrow mesenchymal cells• Umbilical cord cells • Adipose tissue stroma cells• Mesothelial cells (from epiploon)• Menstrual blood endometrial cells• Stem cells from the testis• Embryonic cells (pluripotents)
BONE MARROW ASPIRATION
DEVELOPMENT OF
BIO-ARTIFICIAL MYOCARDIUM
BACKGROUNDLimitations of Cellular Cardiomyoplasty
• Cell bio-retention and engraftment within scar tissue is low
• Mortality of implanted cells in ischemic myocardium is high
• In ischemic heart disease the extracellular matrix is pathologically modified
BACKGROUND 2Limitations of Cellular Cardiomyoplasty
• Implanted cells lack both mechanical synchronization and electrical integration, forming « islands of tissue »
Questions and risks:• Excitation-contraction coupling?• Additional excitable cells?• Proarrhythmic?
RATIONALE FOR 3D CARDIAC TISSUE ENGINEERING
• The efficacy and arrhythmia occurrence of stem cell therapy depends on the surviving cell number as well as the delivery route of cells
• A cell-seeded epicardial scaffolds should offert additional niches for cell homing without the risk of a proarrhythmogenic substrate
• Allogeneic cells should be better tolerated in a matrix « niche environment »
Heart extracellular
matrix
Cell niche + cell homing
ml : muscular lacunaecl : capillary lacunae
COMPONENTS OF EXTRACELLULAR MATRIX IN HUMAN HEART
Collagen Type I (80%) : Ventricular chamber geometry, structural support
Collagen Type III (10%): Role in transduction of myocyte shortening during systole
EXTRACELLULAR MATRIX IN ISCHEMIC HEART DISEASE
Collagen Type I : Decreases from 80% to 40%
Collagen Type III : Increases from 10% to 35%
RESULTS : Ventricular dilatation, systolic + diastolic dysfunctions
COLLAGEN TYPE I MATRIX (Pangen 2, France)lyophilised, bovine collagen, 5 x 7 x 0.6 cm
DEVELOPMENT OF ARTIFICIAL MYOCARDIUM
• Collagen matrix (type I)
• 3D and Biodegradable
• Seeded with stem cells
Collagen Matrix without cells seeded with cells
Confocal Microscopy
3D matrix + cells
MATRIX
MATRIX GRAFTED ON EPICARDIUM
PRECLINICAL STUDIESPublished in Tissue Engineering 2007; 13:2681-7
Cell-seeded collagen matrix - 2 Mo Follow-up
BIOARTIFICIAL MYOCARDIUM « MAGNUM » Clinical Trial
M yocardialA ssistance byG rafting aN ew bioartificialU pgradedM yocardium
Rationale
Associate a procedure for myocardial and extracellular matrix regeneration, i.e.
Cellular cardiomyoplasty+
Collagen scaffold grafting
Cellular CMP + Cell Seeded Matrix
Clinical Collagen Matrix Implantation
MAGNUM Clinical Trial
RESULTS
Functional Outcomes: 1 year follow-upFunctional Outcomes: 1 year follow-up
Baseline End FU
p =0.005
NYHA Class
0
5
10
15
20
25
30
35
Baseline End FU
p = 0.04
LV Ejection Fraction (%)
Echocardiographic Study
p = 0.03
100
110
120
130
140
150
Baseline End FU
LV End Diastolic Volume (mL)
Echocardiographic Study
120
130
140
150
160
170
180
190
200
Baseline End FU
LV FILLINGDoppler-derived mitral deceleration time (ms)
p = 0.01
DIASTOLIC FUNCTION
0
2
4
6
8
10
Baseline End FU
Scar Area Thickness (mm)
p = 0.005
Echocardiographic Study
Cellular CMP + MatrixRadioisotopic SPECT sestamibi studies Preop 12 Months
MAGNUM CLINICAL TRIALCONCLUSIONS
• REDUCES THE SIZE AND FIBROSIS OF INFARCT SCARS
• MINIMIZES GLOBAL VENTRICULAR DILATATION
• IMPROVES DIASTOLIC FUNCTION
• INCREASES MYOCARDIAL WALL THICKNESS
• INDUCES MODULATION OF EXTRACELLULAR MATRIX
MAGNUM CLINICAL TRIALCONCLUSIONS
• The implanted matrix contributed to generate the “adequate niche” for native, transplanted and migrating stem cells
FUTURE MATRIX IMPROVEMENTS
• Crosslinking angiogenic growth factors
• Prolong absorption delay by nanotechnologies and additional chemical - physical crosslinking
• Stem cell preconditioning : hypoxic conditions (5%) during culturesin-vitro electrostimulation
Nature Clin Pract Cardiovasc Med 2009; 6: 240-9
Use of arginine-glycine-aspartic (RGD) acid adhesion peptides coupled with a new
collagen scaffold to engineer a myocardium-like tissue graft
Schussler O, Coirault C, Louis-Tisserand M, Chachques JC, Carpentier A, Lecarpentier Y
Frontiers in Bioscience. 2009; 14: 2996-3002
Cardiac pre-differentiation of human mesenchymal stem cells
by electrostimulation
Genovese J, Spadaccio C, Schussler O, Carpentier A, Chachques JC, Patel AN
Biomaterials. 2009; 30: 1156-65
The effect of self-assembling peptide nanofiber scaffolds on
mouse embryonic fibroblast implantation and proliferation
Degano IR, Quintana L, Semino C, et al.
A prototypic synthetic extracellular matrix
•Molecular designed material•Chemically defined•Synthetic process•Highly similarity to natural ECMs
structure: nano-scale fibersself-assembling processbiologically permissive non-competition with natural ECMbiodegradableMechanical properties for soft tissues
•Modification control Building up properties•Transient scaffold•Injecting biological material
A generic peptide scaffold network
Peptide nanofibers = 10-20 nmScaffold pore size = 50-200 nm
RECATABI PROJECT - European Union
RECATABI PROJECT - European Union
CARMAT ( Carpentier - Matra )Artificial Heart